Wikipedia

Phenibut

Phenibut,sold under the brand nameAnvifenamong others,[1]is acentral nervous system(CNS)depressantwithanxiolyticeffects, and is used to treatanxiety,insomnia,and for a variety of other indications.[5]It is usually takenorally(swallowed by mouth), but may be givenintravenously.[6][5]

Phenibut
Clinical data
Trade namesAnvifen, Fenibut, Noofen, others[1]
Other namesAminophenylbutyric acid; Fenibut; Fenigam; Phenigam; Phenybut; Phenygam; Phenylgamma; Phenigama; PHG; PhGABA; β-Phenyl-γ-aminobutyric acid; β-Phenyl-GABA[2]
Dependence
liability		Moderate
Addiction
liability		Moderate
Routes of
administration		Common:Oral[3]
Uncommon:Rectal[3]
Drug classGABABreceptor agonist;Gabapentinoid
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability≥63% (250 mg)[5]
MetabolismLiver(minimal)[6][5]
MetabolitesInactive[6]
Onset of actionOral:2–4 hours[3]
Rectal:20–30 minutes[3]
Eliminationhalf-life5.3 hours (250 mg)[5]
Duration of action15–24 hours (1–3 g)[3]
ExcretionUrine:63% (unchanged)[5]
Identifiers
  • 4-Amino-3-phenylbutanoic acid
CAS Number
PubChemCID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.012.800Edit this at Wikidata
Chemical and physical data
FormulaC10H13NO2
Molar mass179.219g·mol−1
3D model (JSmol)
Melting point253 °C (487 °F)
  • O=C(O)CC(c1ccccc1)CN
  • InChI=1S/C10H13NO2/c11-7-9(6-10(12)13)8-4-2-1-3-5-8/h1-5,9H,6-7,11H2,(H,12,13)checkY
  • Key:DAFOCGYVTAOKAJ-UHFFFAOYSA-NcheckY
(verify)

Side effects of phenibut can includesedation,sleepiness,nausea,irritability,agitation,dizziness,euphoria,and sometimesheadache,among others.[6][7]Overdoseof phenibut can produce marked central nervous system depression includingunconsciousness.[6][7]The medication is structurally related to theneurotransmitterγ-aminobutyric acid(GABA), and hence is aGABA analogue.[5]Phenibut is thought to act as aGABABreceptoragonist,similarly tobaclofenandγ-hydroxybutyrate(GHB).[5]However, at low concentrations, phenibut mildly increases the concentration ofdopaminein the brain, providingstimulatoryeffects in addition to theanxiolysis.[8]

Phenibut was developed in theSoviet Unionand was introduced for medical use in the 1960s.[5]Today, it is marketed for medical use in Russia, Ukraine, Belarus, Kazakhstan, and Latvia.[5]The medication is not approved for clinical use in the United States and most of Europe, but it is sold on the Internet as asupplementand purportednootropic.[3][9]Phenibut has been usedrecreationallyand can produceeuphoriaas well asaddiction,dependence,andwithdrawal.[3]It is acontrolled substancein Australia, and it has been suggested that its legal status should be reconsidered in Europe as well.[3]In Germany, phenibut is not approved as a drug and, as a food supplement, is controlled under the German New Psychoactive Substances Act.[10]

In a 2023 assessment, the U.S.Food and Drug Administration(FDA) determined that phenibut does not meet the definition of a dietary ingredient, thereby making phenibut supplement products misbranded and illegal for marketing.[11]FDA warning lettershad been issued to supplement manufacturers marketing phenibut products asadulterated.[12]

Medical uses

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Phenibut is used in Russia, Ukraine, Belarus and Latvia as apharmaceutical drugto treatanxietyand to improvesleep(e.g., in the treatment ofinsomnia).[5][6]It is also used for various other indications, including the treatment ofasthenia,depression,alcoholism,alcohol withdrawal syndrome,post-traumatic stress disorder,stuttering,tics,vestibular disorders,Ménière's disease,dizziness,for the prevention ofmotion sickness,and for the prevention of anxiety before or aftersurgical proceduresor painfuldiagnostic tests.[6][5]

Available forms

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Phenibut is available as a medication in the form of 250 mg or 500 mgtabletsfororal administrationand as asolutionat aconcentrationof 10 mg/mL forinfusion.[6][7][13]In the US, dietary supplements labeled as containing phenibut have been found to contain zero to greater than 1,100 mg of phenibut per serving.[9]

Contraindications

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Contraindicationsof phenibut include:[6][7]

Phenibut should not be combined withalcohol.[7]

Side effects

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Phenibut is generally well-tolerated.[5][7]Possibleside effectsmay includesedation,somnolence,nausea,irritability,agitation,anxiety,dizziness,headache,andallergic reactionssuch asskin rashanditching.[6][7]At high doses,motor incoordination,loss of balance,andhangoversmay occur.[3]Due to its CNS depressant effects, people taking phenibut should refrain from potentially dangerous activities such as operating heavy machinery.[6][7]With prolonged use of phenibut, particularly at high doses, theliverandbloodshould bemonitored,due to risk offatty liver diseaseandeosinophilia.[6][7]

Overdose

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Inoverdose,phenibut can cause severedrowsiness,nausea,vomiting,eosinophilia,lowered blood pressure,renal impairment,and, above 7 grams,fatty liver degeneration.[6][7]There are no specificantidotesfor phenibut overdose.[7]Lethargy,somnolence,agitation,delirium,tonic–clonic seizures,reduced consciousness or unconsciousness,andunresponsivenesshave been reported in recreational users who have overdosed.[3]Management of phenibut overdose includesactivated charcoal,gastric lavage,induction of vomiting, and symptom-based treatment.[6][7]There have been three associated deaths which found Phenibut in the users system but only one of these cases single-handedly included Phenibut.[14]

Dependency and withdrawal

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Toleranceto phenibut easily develops with repeated use leading to dependency.[5][needs update]Withdrawalsymptomsmay occur upon discontinuation, and, in recreational users taking high doses, have been reported to include severe rebound anxiety,insomnia,anger,irritability, agitation,visualandauditory hallucinations,and acutepsychosis.[3]Baclofen has successfully been used for treatment of phenibut dependence.[15]

Interactions

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Phenibut may mutually potentiate and extend the duration of the effects of other CNS depressants, includinganxiolytics,antipsychotics,sedatives,opioids,anticonvulsants,andalcohol.[6][7]

Pharmacology

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See also:Gabapentinoid § Pharmacology

Pharmacodynamics

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GABA and analogues
at biological targets[16]
Compound GABAB GABAA
GABATooltip γ-Aminobutyric acid 0.08 0.12
GHBTooltip γ-Hydroxybutyric acid >100 >100
GABOBTooltip γ-Amino-β-hydroxybutyric acid 1.10 1.38
Phenibut 9.6 >100
4-F-phenibut 1.70 >100
Baclofen 0.13 >100
(R)-Baclofen 0.13 >100
(S)-Baclofen 74.0 >100
Values areIC50(μM) in rat brain.

Phenibut acts as afull agonistof theGABABreceptor,similarly tobaclofen.[17][18]It has between 30- and 68-fold loweraffinityfor the GABABreceptor than baclofen, and, in accordance, is used at far higher doses in comparison.[17](R)-Phenibut has more than 100-fold higher affinity for the GABABreceptor than does (S)-phenibut; hence, (R)-phenibut is the active enantiomer at the GABABreceptor.[19]


Phenibut and analogues
at biological targets[20]
Compound α2δ GABAB
Phenibut ND 177
(R)-Phenibut 23 92
(S)-Phenibut 39 >1,000
Baclofen 156 6
Gabapentin 0.05 >1,000
Values are Ki(μM) in rat brain.

Phenibut also binds to and blocksα2δ subunit-containing VDCCs, similarly togabapentinandpregabalin,and hence is agabapentinoid.[20][21]Both (R)-phenibut and (S)-phenibut display this action with similaraffinity(Ki= 23 and 39 μM, respectively).[20]

It is often claimed on websites aboutnootropicsand elsewhere on the internet that phenibut increases dopamine. Three papers published in Russian by Soviet scientists in 1979, 1986, and 1990 report that phenibut increases dopamine in the striatum of rats and in the mouse brain.[22]The mechanism underlying this putative effect is unclear.[22]Structurally, phenibut can also be considered a derivative ofphenethylamine,and some research suggests that phenibut antagonizes the action of phenethylamine.[22]

Pharmacokinetics

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Little information thus far has been published on the clinicalpharmacokineticsof phenibut.[5]The drug is reported to be well-absorbed.[6]Itdistributeswidely throughout the body and across theblood–brain barrier.[6]Approximately 0.1% of an administered dose of phenibut reportedly penetrates into thebrain,with this said to occur to a much greater extent in young people and the elderly.[6]Following a single 250 mg dose in healthy volunteers, itselimination half-lifewas approximately 5.3 hours and the drug was largely (63%)excretedin theurineunchanged.[5]

Some limited information has been described on the pharmacokinetics of phenibut in recreational users taking much higher doses (e.g., 1–3 grams) than typical clinical doses.[3][23]In these individuals, theonset of actionof phenibut has been reported to be 2 to 4 hours orally and 20 to 30 minutesrectally,thepeak effectsare described as occurring 4 to 6 hours following oral ingestion, and the totaldurationfor the oral route has been reported to be 15 to 24 hours (or about 3 to 5 terminal half-lives).[3]

Chemistry

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Phenibut is asyntheticaromatic amino acid.It is achiral moleculeand thus has two potentialconfigurations,as (R)- and (S)-enantiomers.[18]

Structure and analogues

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Chemical structures of phenibut and analogues.

Phenibut is aderivativeof theinhibitoryneurotransmitterGABA.[5]Hence, it is aGABA analogue.[5]Phenibut is specifically theanalogueof GABA with aphenyl ringsubstituted in at the β-position.[5]As such, its chemical name is β-phenyl-γ-aminobutyric acid, which can be abbreviated as β-phenyl-GABA.[5]The presence of the phenyl ring allows phenibut to cross theblood–brain barriersignificantly, unlike GABA.[5]Phenibut also contains thetrace amineβ-phenethylaminein itsstructure.[5]

Phenibut is closely related to a variety of other GABA analogues includingbaclofen(β-(4-chlorophenyl)-GABA),4-fluorophenibut(β-(4-fluorophenyl)-GABA),tolibut(β-(4-methylphenyl)-GABA),pregabalin((S)-β-isobutyl-GABA),gabapentin(1-(aminomethyl)cyclohexane acetic acid), andGABOB(β-hydroxy-GABA).[5][20]It has almost the same chemical structure as baclofen, differing from it only in having ahydrogenatom instead of achlorineatom at theparaposition of the phenyl ring.[5]Phenibut is also close in structure to pregabalin, which has anisobutylgroup at the β position instead of phenibut's phenyl ring.[20]

Aglutamate-derivative analogue of phenibut isglufimet(dimethyl 3-phenylglutamate hydrochloride).[24]

Synthesis

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Achemical synthesisof phenibut has been published.[13]

History

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Phenibut was synthesized at theA. I. Herzen Leningrad Pedagogical Institute(USSR) by ProfessorVsevolod Perekalin's team and tested at the Institute of Experimental Medicine, USSR Academy of Medical Sciences.[5]It was introduced into clinical use in Russia in the 1960s.[5]

Society and culture

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Olainfarm's pharmaceutical phenibut sold in Russia.

Other names

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Alternate spellings includefenibutandphenybut.[2]It is also sometimes referred to asaminophenylbutyric acid.[1]The wordphenibutis a contraction of the chemical name of the drug,β-phenyl-γ-aminobutyric acid.[5]In early publications, phenibut was referred to asfenigamandphenigama.[5][25]The drug has not been assigned anINNTooltip International Nonproprietary Name.[2][6]

Brand names

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Phenibut is marketed inRussia,Ukraine,Belarus,andLatviaunder the brand names Anvifen, Fenibut, Bifren, and Noofen (Russian:Анвифен, Фенибут, Бифрен and Ноофен, respectively).[1]

Availability

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Phenibut is approved inRussia,Ukraine,Belarus,andLatviafor medical use.[3]It is not approved or available as amedicationin other countries in theEuropean Union,theUnited States,orAustralia.[3]In countries where phenibut is not a licensed pharmaceutical drug, it is sold onlinewithout a prescriptionas a "nutritional supplement".[3][9]It is often used as a form ofself-medicationforsocial anxiety.[3]

Recreational use

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Phenibut is usedrecreationallydue to its ability to produceeuphoria,anxiolysis,and increasedsociability,[3]as well as remaining undetected in routine urinalysis. Because of its delayed onset of effects, first-time users often mistakenly take an additional dose of phenibut in the belief that the initial dose did not work.[3]Recreational users usually take the drugorally;there are a few case reports of rectal administration and one report ofinsufflation,which was described as "very painful" and causing swollennostrils.[3]

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As of 2021, phenibut is acontrolled substancein Australia,[3]France,[26]Hungary,[27]Italy,[28]Lithuania,[29][30]and Germany[10]where, nevertheless, it is readily obtained online.[31]

In 2015, it was suggested that the legal status of phenibut in Europe should be reconsidered due to its recreational potential.[3]In February 2018, the AustralianTherapeutic Goods Administrationdeclared it a prohibited (schedule 9) substance, citing health concerns due to withdrawal and overdose.[32][33]

As of 14 November 2018, Hungary added phenibut and 10 other items to its New Psychoactive Substances ban list,[34]and, as of 26 August 2020, Italy added phenibut to its New Psychoactive Substances ban list.[28]As of 18 September 2020, France added phenibut to the controlled psychoactive substances list, prohibiting production, sale, storage, and use.[35]

In the United States, phenibut is an unapproved drug, but is often misleadingly marketed as a dietary supplement. It is readily available without a prescription.[36][37]

InAlabama,phenibut was made aSchedule II substanceat the state level in November 2021.[38]

See also

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References

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  2. ^abcElks J (14 November 2014).The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies.Springer. pp. 69–.ISBN978-1-4757-2085-3.
  3. ^abcdefghijklmnopqrstuvOwen DR, Wood DM, Archer JR, Dargan PI (September 2016). "Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity".Drug and Alcohol Review.35(5):591–6.doi:10.1111/dar.12356.hdl:10044/1/30073.PMID26693960.
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  15. ^Samokhvalov AV, Paton-Gay CL, Balchand K, Rehm J (February 2013)."Phenibut dependence".BMJ Case Reports.2013:bcr2012008381.doi:10.1136/bcr-2012-008381.PMC3604470.PMID23391959.
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  17. ^abGABAb Receptor Pharmacology: A Tribute to Norman Bowery: A Tribute to Norman Bowery.Academic Press. 21 September 2010. pp. 25–.ISBN978-0-12-378648-7.
  18. ^abDambrova M, Zvejniece L, Liepinsh E, Cirule H, Zharkova O, Veinberg G, Kalvinsh I (March 2008). "Comparative pharmacological activity of optical isomers of phenibut".European Journal of Pharmacology.583(1):128–134.doi:10.1016/j.ejphar.2008.01.015.PMID18275958.
  19. ^Allan RD, Bates MC, Drew CA, Duke RK, Hambley TW, Johnston GA, et al. (1990). "A new synthesis resolution and in vitro activities of (R)- and (S)-β-Phenyl-Gaba".Tetrahedron.46(7):2511–2524.doi:10.1016/S0040-4020(01)82032-9.ISSN0040-4020.
  20. ^abcdeZvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Liepins V, et al. (October 2015). "R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects".Pharmacology, Biochemistry, and Behavior.137:23–9.doi:10.1016/j.pbb.2015.07.014.PMID26234470.S2CID42606053.
  21. ^Vavers E, Zvejniece L, Svalbe B, Volska K, Makarova E, Liepinsh E, et al. (November 2016). "The neuroprotective effects of R-phenibut after focal cerebral ischemia".Pharmacological Research.113(Pt B):796–801.doi:10.1016/j.phrs.2015.11.013.PMID26621244.
  22. ^abcLapin, Izyaslav (December 2001)."Phenibut (β-Phenyl-GABA): A Tranquilizer and Nootropic Drug".CNS Drug Reviews.7(4):471–481.doi:10.1111/j.1527-3458.2001.tb00211.x.PMC6494145.PMID11830761.
  23. ^Schifano F, Orsolini L, Duccio Papanti G, Corkery JM (February 2015)."Novel psychoactive substances of interest for psychiatry".World Psychiatry.14(1):15–26.doi:10.1002/wps.20174.PMC4329884.PMID25655145.
  24. ^Perfilova VN, Popova TA, Prokofiev II, Mokrousov IS, Ostrovskii OV, Tyurenkov IN (June 2017). "Effect of Phenibut and Glufimet, a Novel Glutamic Acid Derivative, on Respiration of Heart and Brain Mitochondria from Animals Exposed to Stress against the Background of Inducible NO-Synthase Blockade".Bulletin of Experimental Biology and Medicine.163(2):226–229.doi:10.1007/s10517-017-3772-4.PMID28726197.S2CID4907409.
  25. ^Khaunina RA, Lapin IP (1976). "Fenibut, a new tranquilizer".Pharmaceutical Chemistry Journal.10(12):1703–1705.doi:10.1007/BF00760021.ISSN0091-150X.S2CID29071385.
  26. ^Par[1]Archived8 May 2021 at theWayback MachineLa liste des substances psychotropes
  27. ^"39/2018. (XI. 8.) EMMI rendelet Az új pszichoaktív anyaggá minősített anyagokról vagy vegyületcsoportokról szóló 55/2014. (XII. 30.) EMMI rendelet módosításáról"(PDF).Archived(PDF)from the original on 14 November 2018.Retrieved14 November2018.
  28. ^ab"Gazzetta Ufficiale 11/08/20".Lorenzo Arbolino. 11 August 2020.Archivedfrom the original on 2 May 2024.Retrieved27 August2020.
  29. ^"RINKOS RIBOJIMO PRIEMONĖS FENIBUTUI!".ntakd.lrv.lt(in Lithuanian). Archived fromthe originalon 6 October 2021.Retrieved27 January2020.
  30. ^"V-1431 Dėl Lietuvos Respublikos sveikatos apsaugos ministro 2000 m. sausio 6 d. įsakymo Nr. 5" Dėl Narko... "e-seimas.lrs.lt(in Lithuanian).Archivedfrom the original on 27 January 2020.Retrieved27 January2020.
  31. ^Bonnet U, Scherbaum N, Schaper A, Soyka M (5 April 2024)."Phenibut — an Illegal Food Supplement With Psychotropic Effects and Health Risks".Deutsches Ärzteblatt International.121(7):222–7.doi:10.3238/arztebl.m2024.0003.PMC11539871.PMID38377332.
  32. ^"3.3 Phenibut".Administration Therapeutic Goods Administration.Australian Government Department of Health. 31 October 2017.Archivedfrom the original on 27 March 2020.Retrieved6 November2017.
  33. ^"Mass school overdose investigation focuses on banned Russian drug".ABC News.Australian Broadcasting Corporation. 22 February 2018.Archivedfrom the original on 22 February 2018.Retrieved22 February2018.
  34. ^"EMMI Decree substances or groups of compounds classified as new psychoactive substances".Wolters Kluwer. 1 January 2015. Archived fromthe originalon 8 August 2020.Retrieved5 August2020.
  35. ^"Le phénibut interdit en France | Le Généraliste".Le Généraliste.Archivedfrom the original on 22 January 2021.Retrieved28 April2021.
  36. ^Penzak SR, Bulloch M (June 2024). "Phenibut: Review and Pharmacologic Approaches to Treating Withdrawal".J Clin Pharmacol(Review).64(6):652–671.doi:10.1002/jcph.2414.PMID38339875.
  37. ^Jouney EA (March 2019). "Phenibut (β-Phenyl-γ-Aminobutyric Acid): an Easily Obtainable" Dietary Supplement "With Propensities for Physical Dependence and Addiction".Curr Psychiatry Rep.21(4): 23.doi:10.1007/s11920-019-1009-0.PMID30852710.
  38. ^"Controlled Substances List; Schedule II, page 70"(PDF).Alabama State Board of Health. 22 February 2024.Archived(PDF)from the original on 8 August 2024.Retrieved13 September2024.
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